Base editing repairs mutation and liver function in mouse model of Zellweger spectrum disorder

The authors tested two different base editors in mice — one called ABE8e and a modified version called ABE8e-V106W — and found that both efficiently corrected the PEX1 mutation, but ABE8e-V106W was significantly better tolerated in the animals and made fewer off-target edits. When Kiran Musunuru of the University of Pennsylvania Perelman School of Medicine, one of baby KJ’s lead doctors, asked Liu which deaminase he and his team should use to correct KJ’s disease-causing mutation, Liu recommended ABE8e-V106W based on the data reported in today’s publication.

“These observations, well before the data was published, suggested that ABE8e-V106W is an adenine base editor that sits in the Goldilocks zone, where it offers both high on-target activity that can efficiently correct a pathogenic mutation, and relatively low off-target activity that reduces the frequency of unwanted edits,” said Liu, Richard Merkin Professor, and director of the Merkin Institute for Transformative Technologies in Healthcare at Broad the Dudley Cabot Professor of the Natural Sciences in the Faculty of Arts and Sciences at Harvard University, and Howard Hughes Medical Institute investigator.

“It’s easy to assume that rescuing this quite-rare peroxisome disorder in mice wouldn’t have anything to do with saving a human baby with a very different life-threatening disease. But, it actually had a lot to do with it. It goes to show how science builds on itself, and how sharing the latest unpublished findings at a key moment can inform important decisions in the cutting-edge treatment of patients,” Liu added.

The findings pave a path toward treating the root genetic cause of Zellweger spectrum disorder, a metabolic disease that affects about 1 in 50,000 to 90,000 births in North America.

“Correcting the most common PEX1 mutation is just the beginning of building meaningful treatment strategies for patients with Zellweger spectrum disorder, who currently have no options that treat the cause of the disease,” said lead author Xin “Daniel” Gao, now an Assistant Professor at the University of Pittsburgh, who led the project as a postdoctoral fellow in Liu’s lab. “More broadly, this work lays the foundation for using precision gene editing to develop better treatments for other rare peroxisomal diseases caused by mutations in PEX genes.”

“A great deal of work went into the mouse modeling for this project. Ultimately, we developed a model that faithfully reproduces the disease and its long-chain fatty acid biomarkers, giving us strong confidence that these findings will translate into the clinic. This collaboration between David’s and my labs represents one of many joint efforts and serves as a cornerstone for future therapeutic advances emerging from the Center for Genetic Surgery,” said Lutz, co-senior author of the study and vice president of the Rare Disease Translational Center at Jackson Laboratory.

Translational potential  

In their study, the researchers administered base editors to neonatal and older mice with the PEX1 variant, using two adeno-associated viruses, which delivered the base editors to the livers of the animals. The team revealed that the base editor corrected the PEX1 gene in roughly 60 percent of liver cells, high enough to restore peroxisome and liver function and lower the buildup of toxic metabolites throughout the body.

The scientists also showed that the editing efficiency increased over the duration of the study — a lower dose of base editors was able to achieve the same level of editing over time as the higher dose the team tested.

According to Liu, more research is needed to translate this work in mice into a potential treatment for humans. For example, the authors showed that the base editing system could be reformulated to be delivered using lipid nanoparticles, which have been used in several treatments for humans including KJ’s. However, further optimization of nanoparticle delivery of the base editor to treat Zellweger spectrum disorder (ZSD) remains to be done.

One of Liu’s ultimate goals is to make personalized gene editing treatments accessible to patients on a broader scale through the new Center for Genetic Surgery (CGS) that he co-leads at Broad.

“Currently, candidate CGS programs are ones for which a base or prime editor has been shown to correct a pathogenic mutation back to a healthy sequence, resulting in at least partial rescue of the disease in an animal model,” Liu said. “Demonstrating benefit to animals provides the foundation to move the study towards a clinical trial that we hope will eventually benefit patients with few treatment options.”

“There is an urgent unmet need to develop and implement targeted therapies that address the root causes of thousands of genetic disorders. I am honored that our work on a common form of ZSD may have broader impact across other genetic diseases,” said Hacia, co-senior author and medical geneticist at the Keck School of Medicine of University of Southern California. “Many children with ZSD develop life-threatening liver disease, leading to frequent hospitalizations and a shortened lifespan. We are driven by the hope of changing that reality and look forward to advancing this work into clinical trials to address liver disease in ZSD and related pathologies in other affected organs.”

The study’s co-first authors are Xin “Daniel” Gao of Broad and Maximiliano Presa of Jackson Laboratory, and other co-authors include Nancy Braverman of McGill University and Guangping Gao of University of Massachusetts Chan Medical School.